There is ample evidence that a persistent and generalized immune activation, more than the direct effect of HIV-1 replication, may play a major role in AIDS pathogenesis and peripheral CD4+ T cell depletion. This question needs to be further explored and has important clinical implications, because treatment of immune activation would need to be added to highly active antiretroviral therapy (HAART). Although HAART decreases viral loads to undetectable levels in plasma in many HIV-infected individuals, recent studies indicate that that viral replication likely continues at low levels. This low level viral replication could lead to low persistent immune activation and the possible progression to AIDS. Therefore, to answer the question whether an acute and high or a prolonged viral replication plays a role in the establishment of persistent immune activation, studies need to be done in models where viral replication can be controlled. Two recent findings in our laboratories, the development of a conditional live HIV-1 variant (a dox-dependent HIV-rtTA, in which the replication can be switched on and off by the administration of doxycyline (dox))2, and a novel animal model with a human immune system 3, will allow us to examine the impact of different schemes of viral replication on immune activation and HIV-1 pathogenesis. The present proposal represents a unique collaborative approach to test our hypothesis that persistent immune activation, rather than HIV-1 replication, is a major factor leading to HIV-1 pathogenesis. As Treg play an important role in controlling immune responses, we will also examine the impact of Treg on HIV-1 induced immune activation. It is still unclear whether Treg have detrimental or favorable effects on the immune system during HIV-1 infection. We hypothesize that Treg are dysregulated in HIV-1 infection, resulting in depletion of functional Treg generated in the thymus. A decrease in Treg may lead to immune activation and immunopathology. Specifically we will examine: 1. To evaluate the impact of an inducible HIV-1 on immune activation and pathogenesis in the thymus and periphery of Human Immune System (HIS)-RAG2-/-yc-/- mice. 2. To investigate the role of regulatory T cells (Treg) in controlling HIV-1 induced immune activation. Information gained from the proposed experiments will improve our understanding of the role of persistent immune activation in HIV-1 pathogenesis and has potential implications for novel treatments of HIV-1 infected individuals. [unreadable] [unreadable] [unreadable]